Topical fluoride-antibacterial agent

combined therapy versus topical fluoride

monotherapy in preventing dental caries: a
systematic review and meta-analysis

A. Gupta, S. Sharda, Nishant, N. Shafiq,

A. Kumar & A. Goyal

European Archives of Paediatric

Dentistry

ISSN 1818-6300
Volume 21
Number 6

Eur Arch Paediatr Dent (2020)

21:629-646
DOI 10.1007/s40368-020-00561-7

1 23
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 Author's personal copy
European Archives of Paediatric Dentistry (2020) 21:629–646
https://doi.org/10.1007/s40368-020-00561-7

SYSTEMATIC REVIEW

Topical fluoride‑antibacterial agent combined therapy versus topical

fluoride monotherapy in preventing dental caries: a systematic review
and meta‑analysis
A. Gupta1   · S. Sharda1 · Nishant1 · N. Shafiq2 · A. Kumar1 · A. Goyal1

Received: 26 June 2020 / Accepted: 24 August 2020 / Published online: 1 October 2020
© European Academy of Paediatric Dentistry 2020

Abstract
Purpose  To compare the effectiveness of topical fluoride—antibacterial agent combined therapy versus topical fluoride
monotherapy in preventing dental caries among 1- to 16-year-old children.
Methods  PubMed, EbscoHost, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials were searched
for randomised controlled trials. The trials should have assessed the caries-preventive effectiveness of topical fluoride-
antibacterial agent (Povidone Iodine/Chlorhexidine/Xylitol/Triclosan/Cetylpyridinium Chloride) combined therapy versus
topical fluoride monotherapy among children. Out of 3475 records that were screened, full text of 41 articles was assessed
for potential inclusion. Sixteen trials that fulfilled the eligibility criteria were subjected to qualitative synthesis. The risk of
bias was assessed using the Cochrane Collaboration’s tool. Continuous data from nine trials were pooled using Inverse Vari-
ance test in meta-analysis function of Review Manager (version 5.4). GRADE approach was used to analyse the certainty
of evidence. Statistical heterogeneity was quantified using the I2 statistic. A p-value of < 0.05 was considered as statistically
significant.
Results  With respect to the caries increment, combined therapy showed superior caries-preventive effectiveness than topi-
cal fluoride monotherapy [SMD − 0.12, 95% CI (− 0.2 to − 0.04), p = 0.004; (I2 = 20%, p = 0.29)]. No significant difference
was noted between the two groups for the post-intervention salivary S mutans count [SMD − 0.11, 95% CI (− 0.33 to 0.1),
p = 0.3; (I2 = 0%, p = 0.77)].
Conclusion  The pooled analysis indicates towards an added benefit of topical fluoride-antibacterial agent combined therapy
over topical fluoride monotherapy in preventing dental caries incidence among children. However, the results may be inter-
preted with caution since the evidence generated is of low certainty and is driven by two studies on Xylitol, thus it demands
further good quality trials.

Keywords  Dental caries · Streptococcus mutans · Topical fluoride · Antibacterial agent

Introduction malnutrition, delayed speech development, early tooth loss

Untreated dental caries constitutes a significant public health
problem with a global prevalence of 7.8% and 34.1% in
deciduous and permanent dentition, respectively (Peres et al.
2019). Dental caries is a leading cause of pain, discomfort,
* A. Gupta
arpitg.in@gmail.com
1
Oral Health Sciences Centre, Postgraduate Institute
of Medical Education & Research, Chandigarh, India
2
Department of Pharmacology, Postgraduate Institute
of Medical Education & Research, Chandigarh, India
and loss of school hours in children. Besides, it carries sig-
nificant financial implications associated with its treatment
at any stage of diagnosis (Casamassimo et al. 2009). In
recent years, the management of this global epidemic has
shifted from an exclusively surgical restorative approach to
a medical model based on preventive and minimally invasive
strategies (Pitts 2004).
The anticariogenic potential of fluoride has been a criti-
cal area of research in the past few decades. Strong evi-
dence has been well established in favour of topical fluoride
(TF) application for the prevention and control of dental
caries (Marinho 2009). Fluoride has a multi-pronged caries
inhibitory effect. It strengthens tooth enamel against new

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acid attacks, remineralises lost enamel and inhibits meta-
bolic processes of cariogenic bacteria (Featherstone 1999;
Hamilton 1990; Thylstrup 1990). Although the use of topi-
cal fluoride therapies, like mouthrinses, gels and varnishes
in addition to fluoride toothpaste reduces caries by about
10% compared to toothpaste use alone, the additional cari-
ostatic effects of combined topical fluorides is only slight
and mostly not significant (Marinho et al. 2004). As caries
is a diet-dependent, vertically transmissible, infectious con-
dition, an antimicrobial approach to control the cariogenic
bacteria is believed to be an effective strategy to prevent
and control dental caries (Caufield and Griffen 2000). The
conclusions drawn from International Conference on Novel
Anti-caries and Remineralizing Agents (ICNARA 2008,
2012) suggest that an all-round approach to prevent and
control dental caries must incorporate agents that primarily
target enamel remineralisation and also exhibit substantial
antimicrobial properties (ten Cate 2009; ten Cate, Zaura
2012). Additionally, if the pH of plaque or saliva falls below
4.5, it hampers the remineralisation phase of fluoride action
and any addition of fluoride at this point might not give
additional benefits. The use of fluoride with the addition of
antimicrobials has been suggested to be a cariostatic meas-
ure, being especially beneficial during the state of low pH.
Over the years, caries preventing potential of various
other antibacterial agents, such as Cetylpyridinium Chlo-
ride (CPC), Chlorhexidine, Povidone-Iodine (PI), Triclosan,
Xylitol and essential oils, has been evaluated with varied
outcomes. Cochrane reviews assessing the caries-preventive
effectiveness of individual agents, like Xylitol (Riley et al.
2015) and Triclosan (Riley and Lamont 2013), in children
and adults have not focused on the antibacterial effect of the
combination. Therefore, conclusive evidence is still lack-
ing in regard to the additional benefit brought by combining
these antimicrobial agents with fluoride. Thus, this system-
atic review aims to compare the effectiveness of combined
therapy using TF along with an antibacterial agent (PI/Chlo-
rhexidine/Xylitol/Triclosan/CPC) versus TF monotherapy in
preventing dental caries among 1- to 16-year-old children.
Materials and methods
This systematic review and meta-analysis was registered
with the International prospective register of systematic
reviews (PROSPERO Registration ID: CRD42019145136).
Search strategy
Five databases (PubMed, Web of Science (Core Collec-
tion), EBSCOhost, Scopus and the Cochrane Library) were
searched for articles published till May 2020. Follow-
ing terms were used to search the databases for relevant
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European Archives of Paediatric Dentistry (2020) 21:629–646
articles: ‘Topical Fluoride’, ‘Povidone-Iodine’, ‘Chlorhex-
idine’, ‘Xylitol’, ‘Triclosan’, ‘Cetylpyridinium’, ‘Dental
Caries’, ‘Lactobacillus’ and ‘Mutans Streptococci’. The
search strategy is presented in Table 1. Additional records
were manually searched from cross-references. Grey lit-
erature was searched in OpenGrey and TRIP databases.
A two-phase search strategy was adopted. In the
first phase, two authors, ‘AG1’ and ‘SS’, independently
screened the records based on titles and abstracts. In the
second phase, same authors assessed the full-text arti-
cles for eligibility and final inclusion in the qualitative
and quantitative syntheses. Discrepancies, if any, were
resolved by discussion and consensus.
Inclusion criteria
Randomised controlled trials published in the English
language or those with original English translation were
assessed for potential eligibility. All trials that evalu-
ated the effectiveness of combined therapy (experimen-
tal group) using an antibacterial agent (Povidone-Iodine
/Chlorhexidine/Xylitol/Triclosan/CPC) along with TF as
compared with TF monotherapy (control group) on den-
tal caries and salivary/plaque S mutans count and/or Lac-
tobacillus count among 1- to 16-year-old children were
considered for inclusion. In order to evaluate the added
benefit of the antibacterial agent, only the studies with
identical fluoride exposure in terms of dosage, delivery
vehicle and fluoride concentration in the two groups were
included. The PICOT strategy for the inclusion criteria is
summarised in Table 2.
Exclusion criteria
In vitro studies; animal studies; reviews; letters to the editor;
case report/series and observational studies were excluded.
Any trial with unbalanced co-intervention (i.e. an added
intervention in one group alone) which is likely to impact
the outcome variables in that particular group was excluded.
Outcome variables
In the present study, for a direct evaluation of the caries-pre-
ventive effectiveness, the primary outcome recorded was the
mean increment in dental caries seen at a minimum follow-
up of one year in the combined therapy (TF and antibacte-
rial agent) versus TF monotherapy. The secondary outcomes
assessed were post-intervention mean salivary Streptococ-
cus mutans (S mutans) and Lactobacillus colony counts at a
minimum follow-up of 2 weeks.
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European Archives of Paediatric Dentistry (2020) 21:629–646 631

Table 1  Search strategy showing the total number of results obtained across the five databases
Database Search strategy Number of
search results
obtained

Cochrane (Topical Fluoride) AND ((cetylpyridinium) OR (CPC) OR (povidone iodine) OR (chlorhex- 93

idine) OR (triclosan) OR (xylitol) OR (antibacterial)) AND ((caries) OR (Lactobacillus)
OR (Lactobacilli) OR ((mutans) AND ((Streptococcus) OR (Streptococci)))) in All Text
EbscoHost ((Topical Fluoride) AND ((cetylpyridinium) OR (CPC) OR (povidone iodine) OR (chlorhex- 1038
idine) OR (triclosan) OR (xylitol) OR (antibacterial)) AND ((caries) OR (Lactobacillus)
OR (Lactobacilli) OR ((mutans) AND ((Streptococcus) OR (Streptococci))))) (Dentistry &
Oral Sciences Source, CINAHL Plus with Full Text, OpenDissertations)
PubMed (“fluorides, topical”[MeSH Terms] OR (“fluorides”[All Fields] AND “topical”[All 223
Fields]) OR “topical fluorides”[All Fields] OR (“topical”[All Fields] AND “fluoride”[All
Fields]) OR “topical fluoride”[All Fields]) AND ((“cetylpyridinium”[MeSH Terms] OR
“cetylpyridinium”[All Fields]) OR (“cytidylyl-(3’-5’)-cytidine”[Supplementary Con-
cept] OR “cytidylyl-(3’-5’)-cytidine”[All Fields] OR “cpc”[All Fields]) OR (“povidone-
iodine”[MeSH Terms] OR “povidone-iodine”[All Fields] OR (“povidone”[All Fields]
AND “iodine”[All Fields]) OR “povidone iodine”[All Fields]) OR (“chlorhexidine”[MeSH
Terms] OR “chlorhexidine”[All Fields]) OR (“triclosan”[MeSH Terms] OR “triclosan”[All
Fields]) OR (“xylitol”[MeSH Terms] OR “xylitol”[All Fields]) OR (“anti-bacterial
agents”[Pharmacological Action] OR “anti-bacterial agents”[MeSH Terms] OR (“anti-
bacterial”[All Fields] AND “agents”[All Fields]) OR “anti-bacterial agents”[All Fields]
OR “antibacterial”[All Fields])) AND ((“dental caries”[MeSH Terms] OR (“dental”[All
Fields] AND “caries”[All Fields]) OR “dental caries”[All Fields] OR “caries”[All
Fields]) OR (“lactobacillus”[MeSH Terms] OR “lactobacillus”[All Fields]) OR
Lactobacilli[All Fields] OR (mutans[All Fields] AND ((“streptococcus”[MeSH Terms] OR
"streptococcus"[All Fields]) OR Streptococci[All Fields])))
Scopus ALL ((topical AND fluoride) AND ((cetylpyridinium) OR (cpc) OR (povidone AND iodine) 2623
OR (chlorhexidine) OR (triclosan) OR (xylitol) OR (antibacterial)) AND ((caries) OR
(lactobacillus) OR (lactobacilli) OR ((mutans) AND ((streptococcus) OR (streptococci)))))
Web of science (core collection) ALL FIELDS: ((Topical Fluoride) AND ((cetylpyridinium) OR (CPC) OR (povidone 38
iodine) OR (chlorhexidine) OR (triclosan) OR (xylitol) OR (antibacterial)) AND ((caries)
OR (Lactobacillus) OR (Lactobacilli) OR ((mutans) AND ((Streptococcus) OR (Strepto-
cocci)))))
Total—All databases 4015

Table 2  PICOT strategy
showing the inclusion criteria
Population (P) 1- to 16-year-old children
Intervention (I) Combined therapy using TF along with an antibacterial agent
(Povidone-Iodine/Chlorhexidine/Xylitol/Triclosan/CPC)
Comparator (C) TF monotherapy
Outcome (O) Primary: dental caries
Secondary: CFU of S mutans and Lactobacillus in plaque or saliva
Type of study (T) Randomized controlled trials

Data extraction and quality assessment
Two authors (‘NN’ and ‘AK’) independently extracted data
from each included study on the clinical and methodologi-
cal aspects, such as country of origin, study design, study
site, sample size estimation, age of subjects, treatment regi-
men followed and the reported results––using a specially
designed form. Discrepancies were discussed with ’AG1’
and ‘AG2’ and consensus was reached.
Two authors (‘AG1’ and ‘SS’) scaled the articles for
selection bias, performance bias, detection bias, attrition
bias, reporting bias and other bias based on the Cochrane’s
Collaboration Tool (Higgins et al. 2011). Disagreements,
if any, were resolved after consulting other authors (‘NS’
and ‘AG2’). Besides, the quality of the evidence was
assessed using the GRADE (Grading of Recommenda-
tions, Assessment, Development and Evaluations) Frame-
work (GRADEpro, Version 20. McMaster University,
2014). Based on the five domains (risk of bias, impreci-
sion, inconsistency, indirectness and publication bias) of
the GRADE framework, the certainty in evidence/quality

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632
of evidence was assigned as one among the four levels of
certainty (very low, low, moderate and high).
For quantitative analysis, only those trials that reported
outcomes as continuous data (summarised as mean ± SD)
could be pooled. Owing to variability in reporting of the
outcome variables, results from all the trials could not be
pooled. Because of the different scales used to record the
primary and secondary outcomes among the included stud-
ies, standardised mean difference (SMD) with 95% Confi-
dence Interval (95% CI) statistic was used in Review Man-
ager Version 5.4 for the quantitative analysis (Deeks et al.
2019). p-value of less than 0.05 was considered as statisti-
cally significant. Sub-group analysis was carried out for indi-
vidual antibacterial agents (Chlorhexidine, Povidone-Iodine,
Triclosan and Xylitol). The data (mean ± SD values) of the
two experimental groups administering Chlorhexidine gel in
the study by Sundell et al. (2013) and the three experimen-
tal groups administering Chlorhexidine varnish in the study
by Ribeiro et al. (2008) were combined to form one repre-
sentative experimental group to avoid double counting of
the comparator group in the respective studies (Deeks et al.
2019). Due to the observed clinical heterogeneity across the
included studies with respect to the intervention regimen,
there exists variability in the measured intervention effects
and thus a random effects model using the Inverse variance
method was applied (Deeks et al. 2019). Statistical hetero-
geneity was quantified using I2 statistic, where I2 values over
50% indicated moderate to high heterogeneity (Higgins et al.
2011).
Results
The literature search identified 4015 records which were
transferred into an Endnote Library. Nine records were
added from additional search. After removing 549 dupli-
cates, the titles and abstracts of 3475 studies were screened
in the first phase and 41 studies were subjected to phase
2 full-text screening. Finally, 16 studies were selected for
qualitative analysis and 9 studies were subjected to meta-
analysis. The PRISMA flow diagram is shown in Fig. 1.
Characteristics of included studies
The characteristics of the studies included in the qualita-
tive synthesis are presented in Table 3. Eight studies were
included for the Chlorhexidine group, published between
1998 and 2016. Variation in dosage and form of Chlorhex-
idine application was observed. It has been used in con-
centrations of 0.12% solution (Duarte et al. 2008), 0.12%
gel (Pukallus et al. 2013), 1% gel (Sundell et al. 2013) and
varnish (Ribeiro et al. 2008; Petersson et al. 1998; Naidu
et al. 2016; Paul et al. 2014; Martínez et al. 2012).
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European Archives of Paediatric Dentistry (2020) 21:629–646
Five studies published between years 1995 and 2015
were included in the Xylitol group. Xylitol has been used in
various forms, such as chewing gum (Campus et al. 2009),
toothpaste (Chi et al. 2014; Sintes et al. 1995, 2002) and
gummy bear (Lee et al. 2015). Only one study (Perala and
Bhupathiraju 2016) was included in the Triclosan group that
used a mouthwash containing 0.3% Triclosan. The two stud-
ies included for TF-PI combined therapy had used PI in solu-
tion form (Zhan et al. 2006) and foam form (Xu et al. 2009).
No study was found eligible to be included in the qualitative
review to assess the effectiveness of CPC.
Quality of included trials
Out of the 16 randomised controlled trials included in this
review, only one trial (Perala, Bhupathiraju 2016) was
assessed to have an overall low risk of bias, while two
(Duarte et al. 2008; Xu et al. 2009) were assessed to have an
overall unclear risk of bias. The main reason for the unclear/
high risk of selection bias in all the included trials except in
one trial by Xu et al. (2009) was non-reporting of the method
of random sequence generation or failure for allocation con-
cealment. Since in few trials, the participants and/or person-
nel were not blinded, the trials were assessed to have a high
risk of performance bias (Chi et al. 2014; Paul et al. 2014;
Petersson et al. 1998; Sintes et al. 1995, 2002; Ribeiro et al.
2008; Martínez et al. 2012). Risk of bias for all the included
trials is shown in Fig. 2.
Primary outcome: A total of 2237 participants in the
experimental group and 2205 participants in the control
group were compared for mean dental caries increment in
5 studies included in the meta-analysis. Overall, there was
a significant difference in the primary outcome between
the experimental and control groups favouring combined
therapy [SMD − 0.12, 95% CI (− 0.2 to − 0.04), p = 0.004].
However, this result was driven by two studies on TF-Xylitol
combined therapy by same authors (Sintes et al. 1995, 2002).
The sub-group analysis from the two studies for Chlorhex-
idine (Pukallus et al. 2013; Sundell et al. 2013) did not show
any significant difference. Similar results were reported by
the single study pooled for Povidone-Iodine (Zhan et al.
2006). Statistical heterogeneity among the pooled studies
was not significant (I2 = 20%; p = 0.29). The forest plot for
the primary outcome is shown in Fig. 3.
Secondary outcome: A total of 193 participants in the
experimental group and 163 participants in the control group
were compared for post-intervention salivary mean S mutans
count in the five studies included in the meta-analysis. Over-
all, there was no significant difference between the two
groups [SMD − 0.11, 95%CI (− 0.33 to 0.1), p = 0.3]. None
of the agents in sub-group analysis showed a significant dif-
ference. Heterogeneity among the pooled studies was not
significant (I2 = 0%, p = 0.77) (Fig. 4).
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European Archives of Paediatric Dentistry (2020) 21:629–646 633

Records idenfied through database

searching
(n=4015)
Idenficaon

PubMed: 223 Addional records idenfied through other

Cochrane: 93 sources
Scopus: 2623 (n=9)
EbscoHost: 1038
Web of Science: 38
Screening

Records excluded aer screening

Records screened aer duplicate of tle and abstract
removal (n=3434)
(n=3475)

Full-text arcles excluded

(n=25)
(Reason for exclusion: No. of
Full-text arcles assessed for
Eligibility

arcles excluded)
eligibility 1. No Fluoride exposure in one or
(n=41) both groups: 10
2. Adult populaon: 3
3. Fluoride exposure not similar in
the two groups: 6
4. Study design (split mouth/ non-
randomized): 3
5. Outcome variable (Plaque/
gingival index): 1
Studies included in qualitave 6. Co-intervenon: 1
synthesis 7. Follow up study of already
(n=16) included trial: 1
Chlorhexidine: n = 8
CPC: n = 0
PI: n = 2
Triclosan: n = 1
Xylitol: n = 5
Included

Studies included in quantave

synthesis (meta-analysis)
(n=09)
Chlorhexidine: n = 3
CPC: n = 0
PI: n = 2
Triclosan: n = 1
Xylitol: n = 3

Fig. 1  PRISMA flow diagram showing systematic review process

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Table 3  Characteristics of included studies

634

S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction

13
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

Chlorhexidine
1. Petersson et al. Randomized 12-year-old N = 115 N = 104 Approximal car- 3 years Not addressed Mean + SD of –
(1998) (school class children 1:1 mixture of 0.1% F (Fluor ies incidence caries incre-
units) con- 0.1% F (Fluor protector) ment:
trolled trial protector) applied semi- Experimental:
and Cervitec annually 3.78 + 4.32
(CHX) applied Control:
semi-annually 3.01+ 3.74
p > 0.05
2. Duarte et al. Randomized 11–15 year-old N = 85 N = 85 Mean number of 28 days Not addressed Mean + SD of –
(2008) controlled trial school children 0.05% NaF + 0.05% NaF solu- active carious active carious
0.12% CHX tion applica- lesions Caries lesions:
solution appli- tion once per arrest propor- Experimental
cation once day for 14 tions group:
per day for 14 consecutive Baseline = 6.55
consecutive school days ± 4.23
school days Final =
1.02±1.6
p < 0.05
Control group:
Baseline = 6.49
± 4.45
Final = 0.95 ±
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1.79
p < 0.001
Caries Arrest-
ment propor-
tions:
Experimental
group = 85.3%
Control group =
84.4%
p > 0.05
European Archives of Paediatric Dentistry (2020) 21:629–646
 Table 3  (continued)
S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

3. Ribeiro et al. Randomized 11–16 year old N = 43 N = 12 S mutans (CFU/ 1, 4 and 8 Not addressed – Post interven-
(2008) controlled trial children 1% CHX varnish placebo varnish ml of saliva) weeks after tion salivary S
+ use of 1500 application final applica- mutans count (4
ppm F denti- once a day for tion weeks)
frice 3 consecutive Experimental
days + use of group: 5.42 +
1500 ppm F 0.64
dentifrice Control group:
5.68 + 0.5
p > 0.05
4. Martínez et al. Randomized Mean age: 6.2 + N = 36 N = 37 S mutans (CFU/ 1 week after the Not addressed – Reduction in den-
European Archives of Paediatric Dentistry (2020) 21:629–646

(2012) controlled trial 1.4 years Alternate Weekly topical mg dental final applica- tal biofilm was
application of application of biofilm) tion greater in the
1.23% APF 1.23% APF gel experimental
gel and 1% for four weeks group.
chlorhexidine p > 0.05
varnish for
four weeks
5. Pukallus et al. Randomized 2–4-year-old N = 110 N = 89 Incidence of 2 years None reported. Mean + SD car- Prevalence of
(2013) controlled trial children Tooth brushing Tooth brushing dental caries; ies increment: children with
twice daily twice daily Prevalence of Experimental high S mutans:
with 304% F with 304% F children with group = Experimental
toothpaste and toothpaste S mutans and 3.3±3.2 group = 46%
Author's personal copy

once-daily Lactobacillus Control group = Control group =

application of > ­105 CFU/ 3.0±3.3 47%
0.12% CHX Ml. p > 0.05 p > 0.05
gel Caries Prevalence of
prevalence in children with
control group high Lactobacil-
= 5% lus:
Caries Experimental
prevalence in group = 63%
experimental Control group =
group = 7% 66%
p > 0.05 p > 0.05

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635


Table 3  (continued)
636

S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction

13
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

6. Sundell et al. Randomized 2–5 year old N = 47; Basic N = 41; Basic Mean number 2 years Not addressed Mean + SD ds –
(2013) controlled trial pre-school preventive preventive of decayed increment:
children (mean program (7 program (7 surfaces (ds) Experimental
age: 4 years) times in two times in two group = 2.34
years): (oral years): (oral ± 2.59
health educa- health educa- Control group =
tion, dietary tion, dietary 1.9 ± 1.9
counselling, counselling, p > 0.05
F- varnish F -varnish
application and application
250 ppm F- and 250 ppmF
toothpaste) + -toothpaste)
1% CHX gel
7. Paul et al. Randomized 6–10 year old N = 29; Cervitec N = 17; Placebo S mutans CFU/ 3 months None reported. – Median log CFU
(2014) controlled trial children plus (CHX/T varnish (cavity mL of plaque. of MS:
varnish) + Use varnish–copal Baseline:
of F toothpaste rosin with Experimental:
diethyl ether as 4.28
solvent) + Use Control: 4.33
of F toothpaste 3 months:
Experimental: 4.2
Control: 4.31
p > 0.05
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European Archives of Paediatric Dentistry (2020) 21:629–646
 Table 3  (continued)
S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

8. Naidu et al. Randomized 3–6-year-old N = 20 primary N = 20 primary Reduction in 3 months Not addressed Reduction of –
(2016) controlled trial preschool teeth; Fluoride teeth; Fluoride the number white spot
children with and Chlorhex- varnish appli- of white spot lesions:
incipient idine varnish cation once a lesions; Experimental
lesions. application week for one Mean DIAG- group= 55%
once a month month NOdent scores Control group =
40%
p > 0.05
Reduction
in mean
DIAGNOdent
European Archives of Paediatric Dentistry (2020) 21:629–646

scores:
Experimental
group = 3.9
Control group
= 1.3
p < 0.05
Author's personal copy

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637


Table 3  (continued)
638

S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction

13
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen
Povidone-Iodine
9. Zhan et al. Randomized 2–6-year-old N = 11; N = 11; Change in S 3 weeks and 1 Not addressed Mean dental S mutans:
(2006) controlled trial children Oral prophy- Oral prophy- mutans, Lacto- year caries incre- Experimental
laxis+ laxis+ com- bacillus count ment in one group:
complete plete restora- and incidence year: Mean log CFU/ml
restorative tive therapy+ of dental Experimental at baseline = 6.4
therapy +2-ml 2-ml phosphate caries group = 4.4 ± 1.2
PI application buffer solution ± 5.3 Mean log CFU/ml
+ 1.23% APF application+ Control group = at 3 weeks = 4.7
gel application 1.23% APF gel 5.0 ± 7.8 ± 0.7
for 2 minutes. application for p value > 0.05 Control group:
2 minutes Mean log CFU/ml
at baseline = 6.2
± 1.7
Mean log CFU/ml
at 3 weeks = 5.3
± 2.1
p value > 0.05
Lactobacillus:
Experimental
group:
Mean log CFU/ml
at baseline = 4.0
Author's personal copy

± 1.8
Mean log CFU/ml
at 3 weeks = 1.0
± 1.5
Control group:
Mean log CFU/
ml at
baseline = 3.7
± 2.2
Mean log CFU/ml
at 3 weeks = 1.0
± 1.8;
p value > 0.05
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 Table 3  (continued)
S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

10. Xu et al. (2009) Randomized 6–9-year-old- N = 30; N = 31; Change in S 6 months and 1 Not addressed Mean + SD S mutans:
controlled trial children 10% PI & F - F- foam applica- mutans count year DIAGNOdent Experimental
foam applica- tion once a and mean readings: group:
tion once a week for four DIAGNOdent Experimental Mean + SD log
week for 4 weeks readings and group: CFU/ml at
weeks dental caries Baseline = baseline = 5.76
incidence 17.23 ± 8.53 ± 1.04
At one year = Mean + SD log
14.2 ± 7.29 CFU/ml at 6
Control group: months = 4.74
Baseline = ± 0.77
European Archives of Paediatric Dentistry (2020) 21:629–646

17.78 ± 9.84 Control group:

At one year = Mean + SD log
14.4 ± 6.93 CFU/ml at
p > 0.05 baseline = 6.26
± 1.04
Mean + SD log
CFU/ml at 6
months = 4.74
± 0.76
p > 0.05
Triclosan
11. Perala and Randomized 6-14 years old N = 33; N = 33; Change in mean 15 days Not addressed – Mean + SD
Author's personal copy

Bhupathiraju controlled trial school children Mouthwash Mouthwash CFU counts of Reduction in S
(2016) containing containing S mutans mutans count:
0.2% NaF and 0.2% NaF once Experimental
0.3% Triclosan a day for 14 group I = 6.64
usage once a days ± 6.02
day for 14 days Control group =
6.6 ± 6.0
p-value > 0.05

13
639


Table 3  (continued)
640

S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction

13
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen
Xylitol
12. Sintes et al. Randomized 8–10 year old N = 840; N = 837; Mean DFS 3 years Not addressed Mean + SD –
(1995) controlled trial children Twice daily Twice daily increment DFS incre-
tooth brushing tooth brushing ment:
with toothpaste with toothpaste Experimental
containing containing group = 5 ±
10% xylitol + 1100 ppm F 3.7
1100 ppm F Control group =
5.7 ± 4.1
p value = <
0.05
13. Sintes et al. Randomized 7 to 12-year-old N = 1280; N = 1259; Mean DFS 30 months Not addressed Mean + SD –
(2002) controlled trial children Twice daily Twice daily increment DFS incre-
tooth brushing tooth brushing ment:
with toothpaste with toothpaste Experimental
containing containing group = 1.3 ±
10% xylitol + 1100 ppm F 1.89
1100 ppm F Control group =
1.51 ± 2.0
p value = <
0.001
14. Campus et al. Randomized 7–9 year old N = 80; N = 85; Concentration 3 months None reported – Mean + SD
(2009) controlled trial Xylitol chew- Placebo chew- of S mutans in log CFU/ml S
Author's personal copy

ing gum + ing gum + saliva mutans in saliva

fluoridated fluoridated Baseline
toothpaste con- toothpaste con- Experimental
taining 1450 taining 1450 group: 5.37 +
µg/g NaF) µg/g NaF) 2.81
Control group:
5.36 + 1.88
After 3 months
Experimental
group: 5.28 +
5.37
Control group:
5.36 + 1.84
p < 0.05
European Archives of Paediatric Dentistry (2020) 21:629–646
 Table 3  (continued)
S. no. Author Study design Study popula- Experimental Control group Outcome vari- Follow-up Adverse drug Summary of findings
Year tion group Number of sub- ables reaction
Number of sub- jects analysed Dental caries Bacterial count
jects analysed (N); Intervention
(N); Intervention regimen
regimen

15. Chi et al. (2014) Cluster rand- 4–5 year old N = 95 N = 101 Caries incre- 6 months None reported Mean + SD Mean + SD S
omized con- school children Toothpaste Toothpaste con- ment (dmfs); dmfs incre- mutans count
trolled trial Experimental containing taining 1400 S mutans reduc- ment: reduction:
group = 95 1400 ppm ppm F +5% tion Experimental Experimental
Control group F and 31% NaF varnish group = 2.5 group = 0.9
= 101 xylitol + 5% application ± 2.8 ± 0.8
NaF varnish every three Control group = Control group =
application months 1.4 ± 2.5 0.9 ± 0.9
every three p > 0.05 p > 0.05
months
16. Lee et al. (2015) Cluster Kindergarten N = 215; N = 212; Change in mean 1 year Not addressed Adjusted mean –
European Archives of Paediatric Dentistry (2020) 21:629–646

(classroom) school children F-toothpaste, F-toothpaste, dmfs/DMFS dmfs differ-

randomized Oral health Oral health score ence between
controlled trial education education Experimental
twice a year, twice a year, group and
5% NaF var- 5% NaF var- control group
nish applica- nish applica- = 0.0 (95% CI
tion twice a tion twice a = − 1.6 to 1.1)
year + two year p > 0.05
gummy bears Adjusted mean
containing 1.3- DMFS differ-
gram xylitol ence between
thrice a day for Experimental
Author's personal copy

nine months group and

control group
= − 0.11 (95%
CI = − 0.21 to
0.00) p > 0.05

APF gel acidulated phosphate fluoride gel, CHX chlorhexidine, DMFSa decayed missing filled surface in permanent teeth, dmfs decayed missing filled surface in primary teeth, DFS decayed
filled surfaces in permanent teeth, DSe decayed surfaces in enamel, F Fluoride, NaF varnish sodium fluoride varnish, PI Povidone Iodine, S mutans Streptococcus mutans
Statistical significance set at p < 0.05

13
641

642
Random sequence generation (selection bias)
Campus et al. 2009
Chi et al. 2014
Duarte et al. 2004
Lee et al. 2015
Martinez et al. 2012
Naidu et al. 2016
Paul et al. 2014
Perala et al. 2016
Petersson et al. 1998
Pukallus et al. 2013
Ribeiro et al. 2008
Sintes et al. 1995
Sintes et al. 2002
Sundell et al 2013
Xu et al. 2009
Zhan et al. 2006
Fig. 2  Risk of Bias assessment of the included randomized controlled
trials
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Certainty of evidence
Blinding of participants and personnel (performance bias)
We adjudged the certainty of the evidence to be low with
respect to dental caries (primary outcome) and very low with
respect to S mutans count (secondary outcome). The cer-
Blinding of outcome assessment (detection bias)
tainty of the evidence was downgraded due to unclear/ high
risk of bias. Moreover, the studies were assessed to exhibit
Incomplete outcome data (attrition bias)
Allocation concealment (selection bias)
serious concerns with respect to ‘indirectness’ due to the
variability in the treatment regimen and follow-up period.
Selective reporting (reporting bias)
Furthermore, the quality of the evidence for the secondary
outcome was downgraded due to ‘imprecision’ owing to the
small sample sizes in the included studies. The summary of
GRADE quality assessment is shown in Table 4.
Discussion
Other bias
In this review, the most commonly used antibacterial
agents––Xylitol, Triclosan, Povidone-Iodine, CPC and
+ ? + + – + + Chlorhexidine––that are being used along with TF have
been included to evaluate the effectiveness of the combined
– – – + – + + therapy versus TF monotherapy in preventing dental caries.
Most of the trials have not addressed the probable adverse
+ ? + + + + +
effects that might be associated with the respective agents.
+ ? + + – + + However, a few trials reported no adverse effects due to the
agents used in the experimental and control groups (Campus
? ? – – + – ? et al. 2009; Chi et al. 2014; Paul et al. 2014; Pukallus et al.
2013).
– – ? ? + – –
Literature suggests that additional topical fluoride therapy
? ? – – + + + along with the recommended daily use of fluoride toothpaste
in children at high risk of dental caries exerts an enhanced
+ + + + + + + caries inhibiting effect compared to fluoride toothpaste use
alone. The updated European Academy of Pediatric Den-
– – – – + + ?
tistry (EAPD) fluoride guidelines also indicate towards sup-
+ ? – + – + + plemental therapy using fluoride gels, rinses and varnishes
(Toumba et al. 2019). However, the size of the estimated
? ? – ? + + + benefit (10% reduction in decayed, missing and filled tooth
surfaces) is not substantial to recommend use of supplemen-
? ? + + – + +
tal topical fluoride therapy (Marinho et al. 2004). Moreover,
? ? + + – + + the association between the use of fluoride supplements and
dental fluorosis cannot be overlooked. Nonetheless, fluoride
? ? ? ? ? + – therapy must take into account cumulative fluoride exposure
especially in young children (Toumba et al. 2019). Thus,
+ ? + + ? + + the use of additional therapies that reduce the cariogenic
? ? + + ? + +
bacterial load (like antibacterial agents) seems to be a viable
option in effectively controlling dental caries (Horst et al.
2018).
The results of the pooled analysis showed significant
caries-preventive effect with a combination of TF and
antibacterial agents compared to TF alone. However,
this significant result in favour of the combined therapy
was driven by two trials that assessed the effect of twice
daily use of 1100  ppm F-10% Xylitol toothpaste over
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Fig. 3  Forest plot showing antibacterial agent-wise sub-group analysis for caries increment

Fig. 4  Forest plot showing antibacterial agent-wise sub-group analysis for post-intervention S mutans count

TF toothpaste alone at a 3-year follow-up among 7- to
12-year-old children (Sintes et al. 1995, 2002). Contrary
to the results reported by these two trials, other trials failed
to demonstrate superiority of TF-Xylitol combination over
TF alone for preventing dental caries (Chi et al. 2014; Lee
et al. 2015). This could be due to variability in the form,
dosage and delivery vehicle used across the studies. Chi
et al. (2014) have used toothpaste containing 31% Xylitol
and 1400 ppm F for six months and have showed no sig-
nificant difference in between the experimental and control
group. Lee et al. (2015) have used gummy bear contain-
ing 1.3gm Xylitol thrice a day for nine months and have
reported no significant difference between the two groups
at the end of one year.
For the secondary outcome, no additional benefit was
observed in using the 1400 ppm F-31% Xylitol toothpaste
on S mutans reduction at 6 months of follow-up(Campus
et al. 2009). This may be attributed to the sub-optimum dos-
age as the bacteriostatic action of Xylitol is evident at doses
of more than 1.7 gm/ day with higher doses of 6gms/ day
for high-risk groups (Stecksen-Blicks et al. 2008; Milgrom
et al. 2009). However, contrary to the results reported by
Chi et al. (2014), Campus et al. (2009) reported superiority
of using 36.6% Xylitol chewing gum five times a day for

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644
Table 4  Quality assessment according to GRADE
Quality assessment Summary of findings
No. of patients Effect
Absolute
No. of Design Combined TF monotherapy Relative Risk with TF
studies therapy (95% Cl) mono-therapy
Primary outcome: dental caries
5 RCT​ 2237 2205 – –
Secondary outcome: S mutans
5 RCT​ 193 163 – –
six months in reducing the cariogenic bacterial load. Thus,
authors suggest that TF and Xylitol combination exerts a
significant caries-preventive effect over TF use alone, when
used at optimum dosage for longer durations. However, the
low quality of the included trials limit the generalisability
of TF-Xylitol combination as a standard caries-preventive
method. These results are also in line with the findings of
a Cochrane review which assessed the effectiveness of TF-
Xylitol combination on dental caries increment (Riley et al.
2015).
To assess the effectiveness of TF-Triclosan combined
therapy, only a single randomised controlled trial could
be included (Perala and Bhupathiraju 2016). There was no
significant difference in the S mutans count reduction in
between the experimental and the control groups. Such a
result can be attributed to the small follow-up period of just
two weeks and further research on this topic is advocated
(Perala and Bhupathiraju 2016). Moreover, with the increase
in concern regarding bacterial resistance to antimicrobials
worldwide, the addition of Triclosan in mouthwashes for
children may not be recommended (Perala and Bhupathiraju
2016). Findings of a Cochrane review by Riley and Lamont
(2013) have also reported no additional benefit of adding
Triclosan to topical fluoride for preventing dental caries.
Sub-group analysis for Povidone-Iodine also yielded
similar results. Zhan et al. (2006) showed no statistically
significant difference in preventing caries incidence after
a single application of 1.23% TF gel and 10% PI versus
1.23% TF gel alone at one-year follow-up period. Xu et al.
(2009) also reported similar results for dental caries experi-
ence in both deciduous and permanent dentition. Similarly,
on pooling the studies for evaluating the post-treatment S
mutans count, no statistically significant differences were
noted between the two groups (Xu et al. 2009; Zhan et al.
2006). Restorations of the carious lesions, extractions of
the carious teeth or creating awareness regarding mainte-
nance of good oral hygiene might have led to a considerable
reduction in the bacterial load in both the experimental and
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Quality
Risk difference with combined therapy
SMD 0.12 lower (0.2 lower to 0.04 lower) ⊕⊕O O
Low
SMD 0.11 lower (0.33 lower to 0.1 higher) ⊕ O OO
Very Low
control groups alike. As opposed to these outcomes, TF-PI
was found to be more effective than TF alone in preventing
new carious lesions and reducing the cariogenic bacterial
count in primary teeth by Milgrom et al. (2011). However,
shorter follow-up, lesser sample size and lack of randomi-
sation limit the generalisability of the results of this quasi-
experimental trial.
The present analysis showed that there was no difference
in between the TF-Chlorhexidine combined therapy and
TF monotherapy in prevention of dental caries. Naidu et al.
(2016) reported that weekly application of TF-Chlorhexidine
varnish is more effective in remineralising incipient carious
lesions than the application of TF varnish alone at a 3-month
follow-up. This is attributed to the increased salivary levels
of calcium, fluoride and phosphate, indicating a beneficial
action of the combined therapy. However, other trials have
not reported any added benefit of Chlorhexidine over fluo-
ride use alone in preventing dental caries incidence (Pukal-
lus et al. 2013; Sundell et al. 2013; Petersson et al. 1998;
Duarte et al. 2008). Authors suggested regular and frequent
sensitisation sessions of children with dental professionals
to be the cause of improvement in both the experimental
and control groups. Duarte et al. (2008) explained that the
lack of any added advantage of 0.12% Chlorhexidine solu-
tion can be due to the bactericidal activity of Chlorhexidine
being limited only to the first 90 min post application after
which there is no further change in the metabolic activity in
dental plaque.
Only one trial has reported superior effectiveness of
combined therapy (1.23% TF gel and 1% Chlorhexidine var-
nish) applied on alternate weeks for one month in reducing
S mutans load (Martínez et al. 2012). In contrast, Pukallus
et al. (2013), Paul et al. (2014) and Ribeiro et al. (2008)
concluded that the additional use of Chlorhexidine along
with the TF application has no added advantage in reducing
the bacterial load. Pukallus et al. (2013) reported a possibil-
ity that tooth-brushing alone might have resulted in caries
prevention and that the additional effect of Chlorhexidine
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European Archives of Paediatric Dentistry (2020) 21:629–646 645
is therefore not apparent. Ribeiro et al. (2008) had done a
three-day intervention that might not be sufficient to exert
a promising effect on reducing the S mutans load. Thus,
the variability in the results obtained might be attributed to
the different dosages and regimen followed across different
studies.
Limitations of this systematic review include the paucity
of randomised controlled trials on the effectiveness of com-
bined therapy using an antibacterial agent (Povidone-Iodine/
Chlorhexidine/Xylitol/Triclosan/CPC) versus TF monother-
apy in preventing dental caries among 1- to 16-year-old chil-
dren. There exists a vast variability in the dosage and inter-
vention regimen across the included studies. In the present
review, even though appropriate method of analysis (ran-
dom effects model using inverse variance method) is used to
counter the clinical heterogeneity present across the studies,
such variability might have brought some inconsistencies in
the results. We did not aim to evaluate the agents in terms of
the delivery vehicles/treatments regimen. Very few clinical
trials (Pukallus et al. 2013; Zhan et al. 2006) have assessed
the effect of combined therapy using an antibacterial agent
along with TF on Lactobacillus colony count and none of
the studies could be included in the quantitative synthesis.
The focus of this review has been the caries preventive
effect of the combined therapy versus TF monotherapy.
However, the present study was not aimed to assess the
possible effects which the antibacterial agent-TF combined
therapy might have exerted on the gingival health and dental
plaque. Similarly, the effectiveness of using herbal agents
was kept out of the scope of this review.
Conclusion and recommendations
Although the pooled analysis significantly favours combined
use of TF with an antibacterial agent over TF use alone in
preventing dental caries among 1- to 16-year-old children,
the results need to be interpreted with caution since this
result is driven by two studies on Xylitol conducted on the
same study population. Moreover, in light of the low-quality
evidence generated, further research is very likely to have an
important impact on the estimate.
There is a need to conduct well-designed trials to guide
future evidence-based preventive strategies for the manage-
ment of dental caries among children.
Scope for future research
1. Adequately powered trials evaluate the caries-preventive
effectiveness of using various antibacterial agents to the
already recommended daily fluoride regimen as well as
the advocated professional fluoride therapy (Fluoride
varnish/fluoride gel) especially in high-risk individuals.
2. Future randomised controlled trials need to keep gener-
alisability as well as internal validity of study in mind
and focus on deriving an appropriate treatment regimen
for the antibacterial agent-TF combined therapy. This
should comprise the adequacy of follow-up period, dos-
age requirement, frequency of application needed and
suitable delivery vehicle separately for primary and
permanent dentition. Feasibility of application in com-
munity programmes and its cost-effectiveness should
further be assessed.
3. Long-term trials should also assess possible adverse
effects as an additional outcome.
Acknowledgements  The authors thank Prof Krishan Gauba (Head,
Oral Health Sciences Centre, Postgraduate Institute of Medical Educa-
tion & Research, Chandigarh) for his contributions in designing this
review and for his constructive inputs on the manuscript.
Compliance with ethical standards 
Conflict of interest  The authors have no conflict of interest to declare.
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